Malignant glioma is the most fatal of all brain cancers. The tumor invades into the surrounding tissue thus limiting complete removal by surgical resection resulting in recurrence. Identifying molecules involved in glioma invasion is an important step to develop rationally targeted effective therapies. We have demonstrated that the expression of Astrocyte Elevated Gene-1 (AEG-1) is increased in malignant glioma and inhibition of AEG-1 significantly decreases invasion and migration properties of malignant glioma cells. AEG-1 exerts its function by activating the NF-kB signaling pathway. In the nucleus, AEG-1 interacts with the p65 subunit of NF-kB as well as with CBP, an activator of transcription that augments NF-kB transcriptional activity. Thus AEG-1 functions as a co-activator of transcription. AEG-1 does not contain any classical DNA-binding domain or transcription activation domain indicating that it exerts its effects predominantly by interaction with other proteins. Additionally, AEG-1 also protects normal astrocytes from serum starvation-induced apoptosis by activating the PI3K/Akt pathway. The long-term objective of the present proposal is to unravel the molecular mechanism of malignant glioma generation and progression so that the garnered information might be exploited to develop novel therapeutic strategies for the more effective management of malignant-diffuse glioma tumors. The immediate objectives of the present proposal are to authenticate the role of AEG-1 in in vivo regulation of glioma invasion by developing an astrocyte-specific AEG-1-overexpresing transgenic mouse, elucidate in detail the molecular mechanism of AEG-1 function, especially in the context of regulation of NF-kB and PI3K/Akt activity and identify critical AEG-1-downstream genes required for migration and invasion of malignant glioma cells. Our proposed studies are innovative because we aim at understanding the functions of a novel gene AEG-1 that plays an essential role in malignant glioma progression. Successful completion of the proposed studies will generate novel insights into malignant glioma pathogenesis with potential to translate into an effective therapy for this aggressive and frequently fatal cancer. PUBLIC HEALTH RELEVANCE: Invasion into surrounding normal brain tissue is an underlying cause for incomplete surgical removal of malignant glioma tumors resulting in recurrence and fatality. Astrocyte Elevated Gene-1 (AEG-1) is overexpressed in malignant glioma tumors and plays an essential role in regulating invasive properties of malignant glioma cells. The proposed studies aim at understanding the molecular mechanism of AEG-1 function, both in vitro and in vivo in transgenic mouse models, which will pave the way for the development of future novel therapies of malignant glioma based on targeted inhibition of AEG-1.